The long-term goal of the experiments described in this proposal is to identify sources of plasticity of voltage-activated calcium (Ca) channels. The N-type Ca channel has been found only in nerve cells and neuronally-derived tissues, is associated with the regulation of neurotransmitter synthesis and release from presynaptic nerve endings, and in turn, is modulated by many of these same neurotransmitters. N-type Ca channels are the most highly modulated Ca channel in the brain in that more pathways exist for modulation of this Ca channel than for any other, and because of this, are thought to play a special role in the brain. N-type Ca channels display endogeous, heterogeneous activity, called modes, where measured unitary conductance and kinetics vary from mode to mode. Each mode can last for seconds to minutes. At least six modes have been identified and are a source of neural plasticity at the level of the N-type Ca channel. The specific aims of this project are to 1) identify the causes of modal gating and permeation of N-type Ca currents that give rise to channel plasticity, 2) determine whether modulation of N-type Ca channel behavior by neurotransmitters and cellular signals alters the frequency of occurrence and/or the biophysical characteristics of these modes, and 3) identify differences between the subunit composition of N-type Ca channels in sympathetic neurons and in the brain and determine whether differences in the expression level of the subunits is an additional source of plasticity.